Redirecting immune signaling with cytokine adaptors 2528

Abstract Description Cytokines coordinate complex immune processes but have pleiotropic effects, which limits their therapeutic utility. We devised an approach to functionalize cytokine antagonists with “adaptors” to deliver a local cytokine agonist signal through induced proximity. Cytokine adaptors can convert immunosuppressive cytokines into immunostimulatory cytokines, or vice versa, by rewiring local cytokine receptor specificity. These molecules are comprised of modular protein units and are engineered to simultaneously block one cytokine while inducing activation of an alternate cytokine pathway. We developed cytokine adaptors that convert IL-10 or TGF-β into IL-2 agonists that reverse T cell inhibition in vitro, with potential applications in cancer therapy. We also engineered adaptors that convert the pro-inflammatory cytokines IL-23 or IL-17 into an immunosuppressive IL-10 signal, which suppressed inflammatory cytokine production in human primary cells. Unlike other methods of immune conversion that require cell engineering, we demonstrate proof of concept for soluble “switch receptors” that leverage endogenous cues from the microenvironment to drive context-specific signaling. We show that this design concept is generalizable for targeting various cytokines and receptors of interest. Funding Sources NIH-RO1-AI51321, HHMI, Hertz Foundation, T32-GM007365. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)